1. Field of Invention
The present invention relates to certain 3-(4,5,6,7-tetrahydroinol-2-ylmethylidene) -2-indolinone derivatives that inhibit kinases, in particular Src kinase. Pharmaceutical compositions comprising these compounds, methods of treating diseases mediated by kinases, in particular Src kinase, utilizing pharmaceutical compositions comprising these compounds, and methods of preparing them are also disclosed.
2. State of the Art
Src is a cytoplasmic tyrosine kinase implicated in tumor growth, angiogenesis, survival, and invasion ((see., Irby and Yeatman. Role of Src expression and activation in human cancer. Oncogene 19: 5636-5642 (2000)). An activated form, v-Src, is a viral oncogene in chickens. Rare point mutations have been identified in advanced colon tumors and endometrial cancer. Src and/or its close relative Yes have been found to be overexpressed and/or activated in breast, colon, pancreatic, head and neck squamous cell carcinoma, hepatocellular carcinoma, and bladder tumors. Src and Yes are more highly activated/expressed in metastases than in primary colon tumors. Src activity is an independent negative predictor for survival in colon cancer. In mice, inhibition of Src via antisense RNA suppresses growth of human colon and ovarian tumor xenografts. Src is also implicated in certain types of bone disorders. For example, genetic ablation of Src in mice results in osteoporosis ((see., Tanaka et al., 1996 and Susa et al. Src inhibitors: Drugs for the treatment of osteoporosis, cancer or both? Trends Pharm. Sci. 489-495 (2000)) and Src has been shown to be critical for osteoclast-mediated bone resorption. Therefore Src is an attractive target for treating certain types of cancers and bone diseases such as osteoporosis.
In one aspect, the present invention relates a compound of Formula (I): 
wherein:
Y is methylene, ethylene, carbonyl, or xe2x80x94COCH2xe2x80x94;
m is 0or 1;
R1 is xe2x80x94S(O)nR5 (where n is 0, 1, or 2 and R5 is alkyl or aralkyl) or xe2x80x94SO2NR6R7 where R6 and R7 are independently hydrogen, alkyl, cycloalkyl, alkoxyalkyl, or hydroxyalkyl;
R2 is hydrogen, alkyl, or hydroxyalkyl;
R3 is alkyl or hydroxyalkyl; or
R2 and R3 together with the nitrogen atom to which they are attached form a heterocycloamino group;
R4 is:
(a) hydrogen;
(b) xe2x80x94PO(OR8)2 where each R8 is independently hydrogen or alkyl;
(c) xe2x80x94COR9 where R9 is alkyl; or
(d) xe2x80x94CHR10NR11R12 where R10 is hydrogen or alkyl, and R11 and R12 are independently hydrogen or alkyl or R11 and R12 together with the nitrogen atom to which they are attached form heterocycloamino; or a pharmaceutically acceptable salt thereof.
In a second aspect this invention is directed to a pharmaceutical composition comprising one or more compound(s) of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
In a third aspect, this invention is directed to a method of treating diseases mediated by abnormal Src kinases (such as Src, Yes, Fyn, Lyn, Lck, in particular Src), activity in an organism, in particular humans, which method comprises administering to said organism a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. Such diseases include by way of example and not limitation, cancers and bone diseases such as osteoporosis. The compounds of this invention can also regulate the activity of other kinases (PKs) such as EGF, Met, HER2, HER3, HER4, IR, IGF-1R, IRR, PDGFRxcex1, PDGFRxcex2, CSFIR, C-Kit, C-fms, Flk-1R, Flk4, KDR/Flk-1, Flt-1, Flt3, FGFR-1R, FGFR-2R, FGFR-3R, FGFR-4R, Frk, Btk, Csk, Abl, ZAP70, Fes/Fps, Fak, Jak, Ack, Blk, Hck, Fgr, Yrk, CDK2 and Raf. Accordingly, the compounds of this invention are also useful in treating diseases in humans which are mediated by these kinases.
In a fourth aspect, this invention is directed to a method of modulating the catalytic activity (e.g., inhibiting the catalytic activity) of Src family of kinases such as Src, Yes, Fyn, Lyn, Lck, in particular Src, using a compound of this invention or a pharmaceutical composition comprising a compound of this invention and a pharmaceutically acceptable excipient. The method may be carried out in vitro or in vivo. The compounds of this invention can also modulat the catalytic acitivities of other PKs, in particular receptor tyrosine kinases (RTKs), non-receptor protein tyrosine kinases (CTKs) and serine/threonine protein kinases (STKs) in vitro and/or in vivo. In particular, the other tyrosine kinases whose catalytic activity is modulated by a compound of this invention is selected from the group consisting of Met, EGF, HER2, HER3, HER4, IR, IGF-1R, IRR, PDGFRxcex1, PDGFRxcex2, CSFIR, C-Kit, C-fms, Flk-1R, Flk4, KDR/Flk-1, Flt-1, Flt3, FGFR-1R, FGFR-2R, FGFR-3R and FGFR-4R. The cellular tyrosine kinase whose catalytic activity is modulated by a compound of this invention is selected from the group consisting of Frk, Btk, Csk, Abl, ZAP70, Fes/Fps, Fak, Jak, Ack, Blk, Hck, Fgr and Yrk. The serine-threonine protein kinase whose catalytic activity is modulated by a compound of this invention is selected from the group consisting of CDK2 and Raf.
In a fifth aspect, this invention is directed to the use of a compound of Formula (I) in the preparation of a medicament useful in the treatment of a disease mediated by abnormal activity of Src family of kinases, in particular Src kinase.
In a sixth aspect, this invention is directed to a method of preparing a compound of Formula (I) which method comprises reacting a compound of formula 1:
where R1 is as defined in the Summary of the Invention, with a 4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde of formula 2: 
where Y, m, and R2 and R3 are as defined in the Summary of the invention, in the presence of a base;
(i) optionally modifying any of the R1-R4 groups; and
(ii) optionally preparing an acid addition salt; and
(iii) optionally preparing a free base.
Lastly, this invention is also directed to a method of identifying a chemical compound that modulates the catalytic activity of a protein kinase utilizing a compound of Formula (I) as a reference which method comprises by contacting cells expressing said protein kinase with said compound or a compound of Formula (I) or its pharmaceutically acceptable salt and then monitoring said cells for an effect.